Triazole Derivatives of 4,7-disubstituted 2 naphthoic acid (PPTN) as P2Y14 Receptor Antagonists


The Molecular Recognition Section of NIDDK announces the availability of a novel triazole-based probes, structures which act as antagonists at human P2Y14 receptors. Although the physiologic functions of this receptor remain undefined, recently it has been strongly implicated in immune and inflammatory responses. Prior work with a 4,7-disubstituted 2 naphthoic acid derivative (PPTN) established the ability to inhibit chemotaxis of human neutrophils in the lung and kidney.

In this series, the triazole moiety is used as a bioisosteric replacement for the naphthoic acid core of PPTN. This substitution imparts more stability. This triazole ring has increased polarity and additional H-bond accepting groups when compared to a naphthalene core. The new triazole scaffold can form additional interactions that stabilize the ligand within the receptor binding pocket. It has also been identified that substitution at the para-position of the phenyl ring is favored.

Potential Commercial Applications: Competitive Advantages:
  • Probe to examine P2Y14 function.
  • Scaffold for SAR studies and drug design.
  • Potential route to target inflammation, potentially including diabetes and asthma.
 
  • Favorable cLogP for lead compound when compared to PPTN.
  • Wide range of functional groups can be used as terminal aryl substituents in the triazole group.
  • P2Y14 affinity in the nM range.


Inventors:

Kenneth Jacobson (NIDDK)  ➽ more inventions...

Evgeny Kiselev (NIDDK)  ➽ more inventions...

Elisa Uliassi (NIDDK)  ➽ more inventions...

Anna Junker (NIDDK)  ➽ more inventions...


Intellectual Property:
US Application No. 62/233,162
PCT Application No. PCT/US2016/053397
US Application No. 15/762,852
Patent protection is being sought for this invention.

Publications:
Junker A, et al. Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists. J Med Chem. 2016 Jul 14;59(13):6149-68. PMID: 27331270
Azroyan A et al. Renal intercalated cells sense and mediate sterile inflammation via the P2Y14 receptor. PLoS One. 2015 Mar 23;10(3):e0121419. PMID: 25799465
Barrett MO, et al. A selective high-affinity antagonist of the P2Y14 receptor inhibits UDP-glucose-stimulated chemotaxis of human neutrophils. Mol Pharmacol. 2013 Jul;84(1):41-9. PMID: 23592514
Sesma JI, et al. UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal. 2016 Jul 15 (Epub ahead of print). PMID: 27421735

Collaboration Opportunity:

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is seeking statements of capability or interest from parties interested in collaborative research to further develop and evaluate small molecules that target the P2Y14 receptor. For collaboration opportunities, please contact Marguerite J. Miller at Marguerite.Miller@nih.gov or 301-496-9003.


Licensing Contact:
Betty Tong, Ph.D.
Email: tongb@niddk.nih.gov
Phone: 301-451-7836

OTT Reference No: E-213-2015-0
Updated: Sep 6, 2016